The key cellular players involved in Kaposi sarcoma herpesvirus (KSHV)-mediated oncogenesis are poorly understood. The Kaposi's sarcoma lesion is an unusual, atypical, cancer, dependent on viral infection and on inflammatory mediators, the source of which are not well understood. We aim to address the gap in knowledge on key cell types and mediators involved in the development of KS disease. We have identified that potent pro-inflammatory mast cells are prominent and activated in all classic KS lesions from skin, gut, lung and lymph nodes. Activation is extensive with large numbers of degranulating or completed degranulated mast cells localized to lesions. Signaling through the high affinity Fc? receptor 1 by antigen-specific IgE cross-linking initiates degranulation and release of pro- inflammatory and angiogenic pre-formed, stored granule contents. Many diseases involving mast cell activation, such as mast cell activation disease, allergy, anaphylaxis and mastocytosis, activators of mast cells, including IgE, can be measured in blood. We hypothesize that KSHV-induced activation of mast cells is modulated in part, by KSHV-specific IgE-mediated degranulation of local mast cells. To test this hypothesis we will use a combination of patient and experimental derived data. Using a unique patient sample set, obtained through the Aids and Cancer Specimen Resource center from the Anti- Retrovirals in Kaposi's sarcoma (ARKS) study recently completed in Uganda, we will evaluate the levels of total and KSHV-specific IgE in patient serum and test the ability of a range of patient sera to activate HMC-1 and LAD-2 mast cells in vitro. Using the corresponding clinical data we will test the hypothesis that IgE levels correlate to severity of KS disease, being highest in those patients with many lesions and symptoms and lowest in those with no or few lesions. These data, in combination with ongoing studies in our laboratory, should provide substantial evidence for the involvement of mast cells in KS pathogenesis. The impact of our anticipated findings would be to provide additional evidence to support of a proof-of principle trial to test the efficacy of mast cell treatment options on KS disease.